Hybrid of itraconazole, cyclosporine or carvedilol with a layered silicate and a process for preparing the same

ABSTRACT

The present invention provides the hybrids wherein itraconazole, cyclosporine or carvedilol are intercalated into the interlayers and/or absorbed onto the surfaces of layered silicates. The hybrids according to the present invention enable the maximization of bioavailability of drugs by dissolving the drugs from the layered silicates. Furthermore, the present invention provides the preparing methods of the hybrids. The process comprises: (1) dispersing a layered silicate in an aqueous solution to form an aqueous solution containing the layered silicate; (2) dissolving a drug in a organic solvent to form an organic solution containing the drug, the organic solvent having a solubility higher than that in the aqueous solution; and (3) mixing and hybridizing in the inerrface of the aqueous solution containing the layered silicate and the organic phase solution containing the drug in order to intercalate the drug into the interlayers of the layered silicate and/or to absorb the drug onto the surface of the layered silicate.

CROSS REFERENCE TO RELATED APPLICATION

This application is a 35 U.S.C. § 371 National Phase Entry Applicationfrom PCT/KR03/01449, filed Jul. 22, 2003, and designating the U.S.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to hybrids of itraconazole, cyclosporineor carvedilol with layered silicate; and the production method thereof.More specifically, the present invention relates to hybrids ofitraconazole, cyclosporine or carvedilol with layered silicate havinggood water solubility and bioavailability, and the production methodthereof.

2. Description of the Related Art

Itraconazole has been well known as one of antifungal agents and is atricyclic azole compound having the formula below (see U.S. Pat. No.3,717,655). The chemical formula is C₃₅H₃₈Cl₂N₈O₄ and named as(±)-cis-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxoran-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazole-3-one.

Itraconazole shows better antifungal effect than any other compoundsowing to its long elimination time in the body and high permeation intoproteins and lipids; however, its solubility is pH-dependent, that is,its solubility is high in acidic conditions, but low in neutral aqueoussolutions. Therefore, in spite of outstanding pharmaceutical effects,itraconazole is hard to make into formulations because of the poorsolubility in aqueous solutions and consequent low bioavailability.

Cyclosporine is a polymeric peptide drug that consists of 11 amino acids(a molecular weight: 1202) and is classified as cyclosporines A, B, C,D, G and the like based upon the structure, while cyclosporine A withthe structure below (chemical formula C₆₂H₁₁₁N₁₁O₁₂) has been widelyused for its pharmaceutical activity. Cyclosporine has been mainly usedfor the purpose of suppressing immune reactions after transplantation oforgans and tissues although it has been also applied for inflammatorydiseases such as rheumatoid arthritis.

Cyclosporine has a cyclic symmetryic structure with 7 out of 11 aminoacids N-methylated. Such a cyclic symmetryic structure results in verylow polarity, leading to extremely low water solubility of this drug(0.04 mg/Ml H₂O, 25° C.). The extremely poor solubility of cyclosporinecauses low bioavailability (approximately 30%) and it is reported thatsuch broad deviations of the bioavailability exist among individuals asmuch as 5-50%. Therefore, various efforts have been made to developimproved pharmaceutical formulations for cyclosporine, focusing on thedevelopment of a method to enhance the solubility of cyclosporine.

Carvedilol is named as (±)-1-(9H-carbazole-4-yloxy)-3-[(2-(2-methoxyphenoxy)-ethyl)-amino]-2-propanol with the chemical formula ofC₂₄H₂₆N₂O₄, molecular weight of 406.48 and the structure below (see U.S.Pat. No. 4,503,067)

This compound is a novel drug with multiple actions, useful in treatingmild to moderate hypertension. Carvedilol is known as a vasodilator anda competitive non-selective β-adrenaline receptor antagonist. Thefunction of carvedilol as a vasodilator results from blockade ofα1-adrenaline receptor and the blocking activity of β-adrenalinereceptor by carvedilol leads to prevention of reflective tachycardiawhen the compound is used for treatment of hypertension. Such multipleactions of carvedilol are based upon the efficacy of the drug as ananti-hypertension agent. In addition, carvedilol is useful in protectingorgans, especially protection of heart because of its anti-oxidativefunctions in reducing free radical-initiated lipid peroxidation. Inaddition, carvedilol is useful in treating congestive heart failure.However, carvedilol has the strong pH-dependent solubility profile,featuring especially poor solubility in the intestinal juice.

The prior conventional methods for enhancing the water-solubility inorder to solve the problems of itraconazole, cyclosporine and carvedilolare divided into two categories. One is to enhance the solubility inaqueous solutions by forming such poorly soluble drugs into liposome,micro-emulsion or emulsion by using surfactants and solvents with goodsolubility for said drugs, as dispersants. The other is to dissolve thepoorly soluble drugs in organic solvents together with hydrophilicpolymers or monomeric compounds which facilitate solving the drugs inthe aqueous solutions; or to mix them at high temperature into solidsolutions of which the water solubility is high.

In the case of itraconazole, Janssen, the original developer of thecapsule formulation, Sporanox®, used a method similar to the latter inthe above to make a formulation of itraconazole. The only differencelies in that the solubility of itraconazole is enhanced by coating thesurfaces of sugar beads of 600-700 μm diameters primarily with a hybridof hydrophilic polymer hydroxypropyl methyl cellulose and itraconazole,and secondarily with polyethylene glycol over the first coating. See WO94/05263 for details. A similar method is disclosed in Korean Patent No.1999-001565 wherein itraconazole is solubilized by melting citric acidinstead of the hydrophilic polymer at 160° C. or dissolving it in themixed solvent of chlorinated methanol and ethanol in an amount equal tothat of itraconazole and then distill the solution under reducedpressure to form a co-melted mixture, and adding appropriate excipientsinto said co-melted mixture. In addition to these, examples in the firstcategory of the aforementioned methods include a method of solubilityenhancing formulation for itraconazole using liposome as disclosed in WO93/15719. In the method disclosed in said publication, itraconazole issolublilized by using phospholipid lecithin as a surfactant, andtetraglycol and dimethyl isosorbid as solvents to form singledouble-layered liposomes containing itraconazole.

Like itraconazole, cyclosporine employs a method fundamentally similarto the above but only with different solubilization process depending onthe characteristics of each drug, or the types and the amount ofsolvents or additives therefor. Korean Laid-open Patent Publication No.1998-0008239 discloses a method for solubilizing cyclosporine by usingcyclic methyl ethylene carbonate or poloxamer 123 as a co-surfactant,vegetable oil (such as corn oil, sesame oil and the like) as oil and asurfactant with HLB (hydrophilic-lipophilic balance) of at least 10.Said composition is designed to solve the problem of low absorption inthe body and delivery of cyclosporine by way of forming micro-emulsionsin which the size of micelle can be controlled to be less than 100 nm.

Solubilization technique of carvedilol has been mainly directed tocontrol the dissolution rate of the drug by using solid solution likecyclosporine or itraconazole. For example, Korean Patent Publication No.2003-0019339 discloses synthesis of solid solution by mixing carvediloland hydrophilic polymer polyethylene glycol at 70° C., and maintenanceof said solid in an amorphous state so as to achieve betterbioavailability than crystalline carvedilol. Another Korean PatentPublication No. 2000-0006503 aims to obtain amorphous carvedilol bysynthesizing solid solution that is formed by addition of oil or fattyacid to said hydrophilic polymers.

Most of the prior arts reviewed in the above have a feature of enhancingabsorption of itraconazole, cyclosporine and carvedilol with temporarysuper-saturation or maximized solubility thereof in gastrointestinaltracts by utilizing polymers and surfactants. However, said techniqueshave shortcomings that pH of the solubilized drugs increase as the drugspass through the gastrointestinal tracts in the state ofsuper-saturation, resulting in re-crystallization of said drugs and thatsuch drugs can be absorbed only within a short period of time.Especially, cyclosporine solubilized in a form of emulsion has itsmaximum solubility instantaneously following the administration and thusit is hard to control the dissolution rate for the optimal absorption inthe gastrointestinal tracts. Therefore, the need still remains todevelop a more effective drug delivery system so as to deliver saiddrugs in the body.

SUMMARY OF THE INVENTION

The present invention provides unique hybrids of drugs having poor watersolubility such as itraconazole, cyclosporine and carvedilol withlayered silicate, which enhance low solubility of these drugs since thedrugs are in the amorphous state in the hybrid and result in varioussolubility and dissolution patterns. Since, from the point ofthermodynamics, compounds or drugs are more stable in crystalline thanin an amorphous form, the solubility of compounds or drugs is usuallyhigher in the amorphous state than in the crystalline state. Consideringsuch theoretical background, the present invention is aimed to elicit atechnique to maintain the amorphous state of the hybrids produced withlayered silicates and drugs such as itraconazole, cyclosporine andcarvedilol.

In preferable embodiments of the present invention, said layeredsilicate is selected from a group of montmorillonite, beidellite andhectorite.

In addition, the present invention provides an appropriate preparingprocess of said hybrids.

More specifically, the present invention provides a preparing process ofhybrids, comprising steps wherein drugs are dissolved in organicsolvents having higher solubility than water and are intercalated intothe interlayer of layered silicates and/or absorbed onto the surfaces ofthe layered silicates through interfacial hybridization by mixing andstirring of the above solution of drugs and the aqueous solutioncontaining the layered silicates.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other features and advantages of the present inventionwill become more apparent by describing in detail exemplary embodimentsthereof with reference to the attached drawings in which:

FIG. 1 shows results of X-ray diffraction data of the hybrids ofitraconazole with montmorillonite;

FIG. 2 shows results of X-ray diffraction data of the hybrids ofitraconazole with hectorite;

FIG. 3 shows the solubility changes with sonication time for thecommercial itraconazole formulation, Sporanox® and the hybrids accordingto the present invention;

FIG. 4 shows concentration change of itraconazole in the bloodrepresenting the bio-absorption characteristic of an itraconazoleformulation;

FIG. 5 shows results of X-ray diffraction data of the hybrids ofitraconazole with magnesium aluminum silicate;

FIG. 6 shows dissolution rate of itraconazole in the pH 1.2 solution forthe hybrids of itraconazole with magnesium aluminum silicate;

FIG. 7 shows results of X-ray diffraction data of the hybrids ofitraconazole with magnesium aluminum silicate having Eudragit E 1000®additionally added;

FIG. 8 shows dissolution rate of itraconazole in the pH 1.2 solution forthe hybrids of itraconazole with magnesium aluminum silicate; thehybrids of itraconazole with magnesium aluminum silicate havingadditional Eudragit E 100®; the hybrids of itraconazole with magnesiumaluminum silicate having additional Eudragit E 100® and hydroxypropylmethyl cellulose (HPMC); and Sporanox

FIG. 9 shows results of X-ray diffraction data of the hybrids ofcyclosporine with montmorillonite; and

FIG. 10 shows results of X-ray diffraction data of the hybrids ofcarvedilol with montmorillonite.

DETAILED DESCRIPTION OF THE INVENTION

Inventors of the present application have found that various dissolutionpatterns of itraconazole, cyclosporine or carvedilol can be achieved byusing hybrids of with layered silicates of said drug and thatbioavailability of said drugs can be maximized by sustained release ofsaid drug from layered silicates under a condition of gastric juice andsubsequently delaying recrystallization of said drug under a conditionof intestinal juice having higher pH than the gastric juice.

The hybrids according to the present invention employ layered silicatesas a carrier for a drug. Hereinafter, more features of silicates areprovided for better understanding, but not intended to limit the scopeof the present invention therein. A structural basis of layeredsilicates is a pyramid form of SiO₄ tetrahedron, in a layeredalumino-silicates, SiO₄ tetrahedron are arranged in a way that twohorizontal sheets of SiO₄ tetrahedron have apexes of tetrahedrons facingeach other and connected by a metal ion (for example, aluminum) so as toform layers of a sandwich structure (for example, Si—Al—Si) alignedperpendicularly one another. Such layered structure enables the ionexchange because SiO₄ tetrahedron, the basis of each layer, can havenegative charge when Si⁺⁴ replaced by Al⁺³. In some cases, the negativecharge results from replacement of Al³⁺ connected by Mg²⁺. To compensatesuch negative charges, cations of alkaline metals or alkaline earthmetals (for example, Na⁺, Ca²⁺ and the like) are present in theinterlayers, wherein such interlayer metal ions are easily substitutedby other cations or cationic organic components compared to metalelements within the layers such as Si, Al, Mg and the like. Moreover,the interlayer cations can be substituted by organic free bases becausethe organic free bases can be also intercalated into interlayers afterreplacing interlayer cations by hydrogen ions. Layered silicatesactually have simultaneous surface adsorption of cationic organiccomponents since the charged surface of the layered silicates as statedabove features adsorption reaction rather than interlayer intercalationreaction when said interlayers exposed to outside. Thus thehybridization of layered silicates with drugs consists ofinterlayer-intercalation and surface-adsorption, wherein the ratiobetween them is responsible for different characteristics in drugdelivery and can be controlled to meet the required characteristics fora drug delivery. In detail, surface-absorbed part of drugs can be easilyseparated and used for the fast release while the interlayerintercalated part is for the sustained release as it takes more time tobe separated than the former, enabling a preferable formulation tocontrol the rate of drug delivery.

Therefore, the hybrid of itraconazole and layered silicates according tothe present invention does not form a crystalline itraconazole since theincreased solubility of itraconazole is essentially due to an amorphousstructure of said hybrids. Said amorphous structure was confirmed byX-ray diffraction analysis showing absence of characteristic peaks forpure crystalline itraconazole. For the production of hybrid ofitraconazole with layered silicates, other drying methods than spraydrying can be used because crystalline itraconazole is not formed duringdrying step even without using spray drying due to the outstandingstability of amorphous itraconazole in the hybrid. Spray drying is usedonly for easy production of fine powder of the hybrid. Same results werealso taken for cyclosporine and carvedilol.

Examples of layered silicates that can be used in the hybrid accordingto the present invention include montmorillonite, beidellite,nontronite, hectorite, saponite, illite, celadonite, glauconite and thelike. Among those montmorillonite, beidellite, hectorite, saponite andillite are preferable. Said compounds are classified into each offormulae 1 to 5 as follows, wherein said formulae represent simplifiedcomposition of actually used layered silicates and are not intended tolimit the compositions of layered silicates therein.(Al_(2-x)Mg_(x))(Si₄)O₁₀[OH]₂M^(+n) _(x/n)   [Formula 1]

(montmorillonite)(Al₂)(Si_(4-x)Al_(x))O₁₀[OH]₂M^(+n) _(x/n)   [Formula 2]

(beidellite)(Mg_(3-x)Li_(x))(Si₄)O₁₀[OH]₂M^(+n) _(x/n)   [Formula 3]

(hectorite)(Mg_(3-x)Fe⁺³ _(x))(Si_(4-2x)Al_(2x))O₁₀[OH]₂M^(+n) _(x/n)   [Formula 4]

(saponite)(Al_(2-x-y)Fe_(y)Mg_(x))(Si_(4-z)Al_(z))O₁₀[OH]₂M^(+n) _((x+z)/n)  [Formula 5]

(illite)

In the above formulae, M stands for an interlayer metal ion, forexample, alkaline metal (example: Na) or alkaline earth metal (example:Ca). x stands for the composition ratio among the interlayer metal ions,preferably from 0.1 to 0.7, more preferably from 0.2 to 0.6 and mostpreferably 0.3 to 0.5.

As stated above, said formulae are simplified only for representativepurpose, wherein the compositions of actually used layered silicates maybe varied to some extents. For example, while the montmorillonite ofFormula 1 has layered structure with tetrahedrons of SiO₄, the naturallyoccurring montmorillonite may contain substitution in the tetrahedronsuch that some of Si are replaced by Al and some of Al connectingtetrahedrons of SiO₄, by other cations with +3 valence(example: Fe⁺³).Such chemical composition can be shown as(Al_(2-x-y)Fe_(y)Mg_(x))(Si_(4-z)Al_(z))O₁₀[OH]₂M^(+n) _((x+z)/n).

The present invention also provides a preparing process of hybrids oflayered silicates with drugs with poor water solubility.

In general, layered silicates may be dispersed well enough in an aqueoussolution and then mixed with a drug of interest to make interlayercations replaced by said drug or to make said drug absorbed onto thesurface of the layered silicates. Considering viscosity and the like, itis preferable to disperse 1 g of montmorillonite per 1 ml of water. Onthe other hand, provided that a single cation in the interlayer of thelayered silicates is substituted with one molecule of itraconazole andthat Formula 1 corresponds to the chemical composition of saidmontmorillonite, the amount of itraconazole required for 1 g ofmontmorillonite is approximately 0.7 g. However, considering that thedrugs of the present invention have extremely low water solubility (forexample, the water solubility of itraconazole is about 1 mg/ml), it ispractically impossible to make the hybrids of itraconazole with layeredsilicates in aqueous solution since it requires thousands of liters ofwater to dissolve such amount of itraconazole.

The present invention thus provides a preparing process of novel hybridsto overcome said problems. The process according to the presentinvention comprises:

(1) dispersing a layered silicate in water to form an aqueous solutioncontaining the layered silicate;

(2) dissolving a drug in a organic solvent to form an organic solutioncontaining the drug, the organic solvent having higher solubility thanthat in aqueous solution; and

(3) mixing and hybridizing in the interface between said aqueoussolution containing the layered silicate and said organic solutioncontaining the drug in order to intercalate said drug into theinterlayers of said layered silicate. The interfacial hybridization inthe above step (3) corresponds to interlayer intercalation/adsorption ofthe drug of interest in the organic phase and the layered silicates inthe aqueous phase through said interface, which is formed in betweensaid aqueous phase containing layered silicates and said organic phasecontaining the drug of interest. Proceeding of the interfacialhybridization through interlayer intercalation/adsorption enablescontinuous supply of the drug of interest from the organic phase intothe aqueous phase until the completion of interlayerintercalation/adsorption between the layered silicates and the drug inthe aqueous phase where the drug of interest is dissolved in anextremely small amount. As explained, the interfacial hybridizationleads to the completion of intercalation/adsorption so as to increasethe contents of the drug of interest in the hybrids and also the yieldof the drugs.

The present invention enables a drug of interest with no charge such asitraconazole to proceed intercalation/adsorption by substituting theinterlayer cations of the layered silicates with hydrogen ions beforethe intercalation/adsorption of step (3) since theintercalation/adsorption does not occur between the drug of interestwith no charge and the layered silicates. For example, in the case ofitraconazole, montmorillonite (hereinafter, MMT) has the interlayercation (M^(+n)) and if substituted with hydrogen ion (H⁺), istransformed from MMT-M^(+n) to MMT-H⁺. Such hydrogen-ionizedmontmorillonite, MMT-H⁺, combines with the amine group (—NH— or —N═) ofitraconazole which is transformed to ammonium group (—NH₂—⁺ or —NH═⁺),resulting in the hybrid of itraconazole with MMT in the form of[MMT-H⁺-itraconazole].

The content of the layered silicates in the aqueous solution of saidlayered silicates is from about 0.1 to about 10 wt. % and morepreferably from about 0.5 to about 3 wt. %. The pH of the solution oflayered silicates ranges from about 0 to about 6 and preferably fromabout 1 to about 4.

The organic solvents used in preparing the above solution containing adrug of interest corresponds to those with higher solubility than thatin aqueous solution for the drug of interest, and the non-aqueoussolvents forming the interface with the aqueous solution. Related to thesolubility of the drug of interest, the organic solvents used havepreferably the solubility 10 times, more preferably 100 times and mostpreferably 1000 times the solubility in said aqueous solutions. Suchorganic solvents include methylene chloride, chloroform, octanol and thelike. Among those methylene chloride and chloroform are preferable andespecially methylene chloride is more preferable.

The amount of the drug in the organic solution can range within thesolubility limit for said drug. Further, the amount of the drug and theamount of the layered silicates depends on the content of the drug inthe hybrid. Thus, the amount of the organic solvent is such to dissolvethe amount of the drug required, and a volume ratio of the aqueoussolvent to the organic solvent in the interface reaction is decidedtherefrom.

According to the present invention the content of the drug of interestin the organic solution ranges: preferably from about 1 to about 30 wt.% and more preferably from about 3 to about 10 wt. %; the volume ratiobetween the aqueous solvent and the organic solvent: preferably about1:10 to about 10:1, more preferably about 1:2 to about 5:1 and mostpreferably 1:1 to about 2:1.

In the hybrids of itraconazole, cyclosporine and carvedilol, withlayered silicates produced according to the present invention, welldeveloped amorphous state provides higher solubility compared to that ofthe crystalline form. However, surface characteristics of the hybridsleads to low wettability of the hybrids in the dissolution medium.Addition of hydrophilic polymers onto said hybrids can lead to increasedwettability of the hybrids in the dissolution medium. Any hydrophilicpolymers are acceptable if there is no pharmaceutical restriction.Preferably Eudragit E100®(butylmethacrylate-(2-dimethylaminoethyl)methacrylatemethylmethacrylate-copolymer) or hydroxypropyl methyl cellulose (HMPC)is selected.

The hydrophilic polymers are added by dissolving said polymers in asuitable solvent (example: methylene chloride and water); and thehybrids are dispersed in the solution and dried. Added amounts of theaqueous polymers are to the extent to provide sufficient wettability tothe hybrids; for example, not less than 0.5 wt. % based on the weight ofdrugs can be used. Drying methods may include various ones known in theart, preferably spray drying.

Hereinafter, example are provided for details of the present inventionbut not intended to limit the scope of the present invention therein.

Hybrid of Itraconazole with Layered Silicates

EXAMPLE 1

10 g of layered silicates, montmorillonite, was added into 1 liter ofdistilled water and stirred for 3 hours, wherein the pH was adjusted to1 using HCl with stirring. Once equilibrium was reached at pH 1, 25 g ofitraconazole was added and completely dissolved in 500 ml of methylenechloride and the solution was combined with the above aqueous solutionof dispersed montmorillonite and then continuously stirred for 24 hoursso as to complete the interlayer intercalation. Following the completionof the intercalation, the aqueous phase and the organic phase wereseparated using centrifugation, and the layered silicates precipitatedin the bottom of the aqueous phase was washed with distilled water atleast twice and then vacuum-dried to obtain the powder form of thehybrid of itraconazole with layered silicates. The X-ray diffractiondata for the hybrids of itraconazole are shown in FIG. 1. Theintercalation of itraconazole into the interlayers of the layeredsilicates was confirmed thereby. The content of the itraconazole in thehybrid was 55 wt. % which was calculated from the element analysis data.

EXAMPLE 2

The hybrid was obtained employing the same conditions as those ofExample 1 except using methylene chloride other than the distilled waterfor 3 times of washing and the content of itraconazole in the hybrid was26 wt. % which was calculated from the element analysis data.

EXAMPLE 3

The hybrid of itraconazole with layered silicates was obtained employingthe same conditions as those of Example 1 except adjusting the pH to 4.The X-ray diffraction data for hybrids of itraconazole are shown inFIG. 1. The intercalation of itraconazole into the interlayers of thelayered silicates was confirmed thereby as done in Example 1 and thecontent of the itraconazole in the hybrid was 55 wt. % which wascalculated from the element analysis data.

EXAMPLE 4

The hybrid of itraconazole with layered silicates was obtained employingthe same conditions as those of Example 1 except using hectorite insteadof montmorillonite as layered silicates. The X-ray diffraction analysisresults for such itraconazole hybrid are shown in FIG. 2. Theintercalation of itraconazole into the interlayers of hectorite wasconfirmed thereby. The content of the itraconazole in the hybrid was 16wt. % which was calculated from the element analysis data.

EXAMPLE 5

The hybrid of itraconazole with layered silicates was obtained employingthe same conditions as those of Example 4 except adjusting the pH to 4.The X-ray diffraction analysis results for hybrids of itraconazole areshown in FIG. 2. The intercalation of itraconazole into the interlayersof the layered silicates was confirmed thereby as done in Example 3. Thecontent of the itraconazole in the hybrid was 15 wt. % which wascalculated from the element analysis data.

EXAMPLE 6

Comparison of the water solubility of itraconazole was made between thehybrids of itraconazole with layered silicates made according to thepresent invention, and the commercial product Sporanox® of Janssen.Sporanox and the hybrids containing 25 and 35 wt. % of itraconazole,respectively, were taken in the amounts corresponding to 100 mg of pureitraconazole; dispersed in 150 ml of the pH 1 aqueous solution;sonicated for 5 minutes; and changes of itraconazole dissolved(presented as percentage of 100 mg itraconazole) in the solution areshown in FIG. 3. The experiment was designed to measure the amount ofthe itraconazole in the solution which is dissolved but notrecrystallized during dissolution. The hybrid with 35 wt. % ofitraconazole showed the similar pattern of solubility to that ofSporanox. Furthermore, the hybrids according to the present inventionsustained its solubility for a period twice as much as that forSporanox. This implies that a period for the absorption of itraconazolein the body can be doubled in the case of the hybrid with 35 wt. %itraconazole.

The hybrid of 25 wt. % itraconazole showed a little increase insolubility but a certain level of solubility is sustained for muchlonger time than Sporanox.

EXAMPLE 7

To evaluate bioequivalence of itraconazole, (A) the hybrid of 26 wt. %itraconazole from Example 2, (B) the hybrid of 66 wt. % itraconazolefrom Example 3, and Sporanox, were orally administered to rats in theamounts corresponding to 5 mg of pure itraconazole and blood was takenat certain times to measure the concentration of itraconazole in theplasma. Results are shown in FIG. 4. Pharmacokinetic parameters such asTmax, Cmax and AUC are shown in Table 1. The solubility pattern forsample (A) shows a considerably low compared to the commercialitraconazole formulation, Sporanox but the actual bioavailability(presented as AUC in Table 1) reaches 90% of that for Sporanox with Tmaxand Cmax similar to those for Sporanox. Sample (B) shows increasedbioequivalence 20% more than that of Sporanox. TABLE 1 Comparison amongthe pharmacokinetic parameters of itraconazole formulations SporanoxHybrid (A) Hybrid (B) T_(max) (hour) 1.8 2.5 1.8 C_(max) (ng/ml) 223 220242 AUC (ng · h/ml) 2630 2378 3327

EXAMPLE 8

10 g of layered silicate, magnesium aluminum silicate, was added into0.5 liter of distilled water and stirred for 3 hours, wherein the pH wasadjusted to 2 using HCl with stirring. Once equilibrium was reached atpH 2, 24 g of itraconazole was added and completely dissolved in 140 mlof methylene chloride and the organic solution was combined with theabove aqueous solution of dispersed magnesium aluminum silicate and thencontinuously stirred for 3 hours so as to complete the hybridization.Following the completion of the hybridization, the aqueous phase in theupper layer of the mixed solution was removed and slurry of hybrids inorganic phase was obtained. The slurry was vacuum-dried so as to obtainthe powder form of the hybrid of itraconazole with layered magnesiumaluminum silicate. The X-ray diffraction data for such itraconazolehybrid are shown in FIG. 5. A specific peak for crystalline itraconazolewas not found and the content of the itraconazole in the hybrid was 55wt. % which was calculated from the element analysis data.

EXAMPLE 9

The hybrid of itraconazole with layered magnesium aluminum silicate wasobtained in the powder form under the same conditions as those ofExample 8 except using 2.6 g of magnesium aluminum by removing the upperaqueous phase and vacuum-drying the lower organic phase during thehybridization. The X-ray diffraction data for such itraconazole hybridare shown in FIG. 5. The content of the itraconazole in the hybrid was55 wt. % which was calculated from the element analysis data.

EXAMPLE 10

The dissolution experiments were performed using the hybrids ofitraconazole with layered magnesium aluminum silicate from Examples 8and 9. The hybrids of 70 and 90 wt. % of itraconazole, respectively,were taken in the amounts corresponding to 100 mg of pure itraconazole;dispersed in 900 ml of the pH 1.2 aqueous solution; stirred in a shakerat 200 rpm; and the concentration changes of itraconazole dissolved fromeach sample are shown in Table 6. The dissolution data of itraconazolefrom the hybrids shown in FIG. 6 confirms itraconazole of the amorphousstate in the hybrid, which coincides with the result that theitraconazole exists in the amorphous state since the X-ray diffractiondata from Table 6 do not show any characteristic peaks of crystallineitraconazole.

EXAMPLE 11

10 g of the powdered hybrid of itraconazole with layered magnesiumaluminum silicate ( 70 wt. % of itraconazole) from Example 8 was addedto 100 ml of methylene chloride, wherein Eudragit E 100 1.4, 3.5 and 6.3g, corresponding to 20, 50 and 90% of pure itraconazole, respectively,were dissolved; stirred for 30 minutes; and spray-dried so as to obtainthe powdered hybrid of itraconazole with layered magnesium aluminumsilicate coated with Eudragit E100.

The X-ray diffraction data for such itraconazole hybrid are shown inFIG. 7. The characteristic peaks of crystalline itraconazole were notobserved from these samples. The contents of the itraconazole in thehybrid were 61.4, 51.9 and 42.9 wt. %, respectively, which werecalculated from the element analysis data.

EXAMPLE 12

Among the samples from Example 11, the hybrid with the ratio 0.9 ofEudragit versus itraconazole was taken and 1 g of HPMC 606 was added to23 g of this hybrid via wet granulation. Granules of hybrid ofitraconazole with layered magnesium aluminum silicate coated withEudragit E100 and HPMC was obtained.

EXAMPLE 13

Comparison of the dissolution rate was made among the samples preparedwithout Eudragit or HPMC according to Example 8; powdered hybrids ofitraconazole with layered magnesium aluminum silicate according toExample 11, wherein the ratio of Eudragit versus itraconazole was 0.2,0.5 and 0.9, respectively; and the sample from Example 12. Each samplecorresponding to 100 mg of pure itraconazole was taken and dispersed in900 ml of the pH=1.2 aqueous solution at the dissolution test apparatus.The solution was stirred at pedal speed of 50 rpm. Aliquots of solutionwere taken every 15 minutes to 30 minutes to measure the amounts ofdissolved itraconazole. The changes of dissolved itraconazole are shownin FIG. 8. Summarizing the results of FIGS. 3 and 6 along with those ofFIG. 8 leads to the conclusion that the hybrids of itraconazole withlayered silicates made according to the present invention, provide anoutstanding method for various dissolution rates which can be controlledupon the dissolution conditions due to prominent stability of amorphousstate of itraconazole and provide various content of itraconazole in thehybrid.

Hybrid of Cyclosporine with Layered Silicates

EXAMPLE 14

10 g of layered silicates, montmorillonite was added into 1 liter ofdistilled water and stirred for 3 hours, wherein the pH was adjusted to4 using HCl with stirring. Once equilibrium was reached at pH 4, 24 g ofcyclosporine was added and completely dissolved in 500 ml of methylenechloride. The organic solution was combined with the aqueous solutionwith dispersed montmorillonite and then continuously stirred for 24hours so as to complete the interlayer intercalation. Following thecompletion of the intercalation, the aqueous phase and the organic phasewere separated using centrifugation, and the precipitates in the bottomof the aqueous phase was washed with distilled water at least twice andvacuum-dried to obtain the powder form of the hybrid of cyclosporinewith layered silicates. The X-ray diffraction data for the hybrid ofcyclosporine are shown in FIG. 9; the intercalation of cyclosporine intothe interlayers of the layered silicates was confirmed thereby; and thecontent of the cyclosporine in the hybrid was 50 wt. % which wascalculated from the element analysis data.

Hybrid of Carvedilol with Layered Silicates

EXAMPLE 15

10 g of montmorillonite was added into 1 liter of distilled water andstirred for 3 hours, wherein the pH was adjusted to 1 using HCl withstirring. Once equilibrium was reached at pH 1, 4 g of carvedilol wasadded and completely dissolved in 200 ml of methylene chloride. Theorganic solution was combined with the aqueous solution with dispersedmontmorillonite and then continuously stirred for 24 hours so as tocomplete the interlayer intercalation. After the completion of theintercalation, the aqueous phase and the organic phase were separatedusing centrifugation, and the precipitates in the bottom of the aqueousphase was washed with distilled water at least twice and vacuum-dried toobtain the powder form of the hybrid of carvedilol with layeredsilicates. The X-ray diffraction data for the hybrid of carvedilol areshown in FIG. 10; the intercalation of carvedilol into the interlayersof the layered silicates was confirmed thereby; and the content of thecarvedilol in the hybrid was 21 wt. % which was calculated from theelement analysis data.

EXAMPLE 16

The hybrid of carvedilol with layered silicates was made under the sameconditions as those of Example 15 except for the change of pH to 2. Thecontent of carvedilol in the hybrid was confirmed to be 25 wt. %.

EXAMPLE 17

The hybrid of carvedilol with layered silicates was made under the sameconditions as those of Example 15 except for the change of pH to 3. Thecontent of carvedilol in the hybrid was confirmed to be 22 wt. %.

EXAMPLE 18

The hybrid of carvedilol with layered silicates was made under the sameconditions as those of Example 15 except dissolving 8.2 g of carvedilolin 200 ml of methylene chloride. The content of carvedilol in the hybridwas confirmed to be 42 wt. % which was calculated from the elementanalysis data.

EXAMPLE 19

The hybrid of carvedilol with layered silicates was made under the sameconditions as those of Example 18 except for the change of pH to 2. Thecontent of carvedilol in the hybrid was confirmed to be 39 wt. %.

EXAMPLE 20

The hybrid of carvedilol with layered silicates was made under the sameconditions as those of Example 18 except for the change of pH to 3. Thecontent of carvedilol in the hybrid was confirmed to be 38 wt. %.

EXAMPLE 21

5g of montmorillonite was added into 1 liter of distilled water andstirred for 3 hours, wherein the pH was adjusted to 1 using HCl withstirring. Once equilibrium was reached at pH 1, 6 g of carvedilol wasadded and completely dissolved in 150 ml of methylene chloride. Theorganic solution was combined with the aqueous solution with dispersedmontmorillonite and then continuously stirred for 24 hours so as tocomplete the intercalation. After the completion of the intercalation,the aqueous phase and the methylene chloride phase were separated usingcentrifugation, and the precipitates in the bottom of the aqueous phasewas washed with distilled water at least twice and vacuum-dried toobtain the powder form of the hybrid of carvedilol with layeredsilicates. The content of the carvedilol in the hybrid was 50 wt. %which was calculated from the element analysis data.

EXAMPLE 22

The hybrid of carvedilol with layered silicates was made under the sameconditions as those of Example 21 except for the change of pH to 2. Thecontent of carvedilol in the hybrid was confirmed to be 44 wt. %.

EXAMPLE 23

The hybrid of carvedilol with layered silicates was made under the sameconditions as those of Example 21 except for the change of pH to 3. Thecontent of carvedilol in the hybrid was confirmed to be 47 wt. %.

EXAMPLE 24

The hybrid of carvedilol with layered silicates was made under the sameconditions as those of Example 21 except for the change of pH to 4. Thecontent of carvedilol in the hybrid was confirmed to be 42 wt. %.

EXAMPLE 25

The hybrid of carvedilol with layered silicates was made under the sameconditions as those of Example 21 except for the change of pH to 5. Thecontent of carvedilol in the hybrid was confirmed to be 37 wt. %.

EXAMPLE 26

10 g of layered silicate, montmorillonite, was added into 1 liter ofdistilled water and stirred for 3 hours, wherein the pH was adjusted to1 using HCl with stirring. Once equilibrium was reached with the pH 1,12 g of carvedilol was added and completely dissolved in 300 ml ofmethylene chloride. The organic solution was combined with the aboveaqueous solution with dispersed montmorillonite and then continuouslystirred for 24 hours so as to complete the intercalation. After thecompletion of the intercalation, the aqueous phase and the methylenechloride phase were separated using centrifugation, and the precipitatesin the bottom of the aqueous phase was washed with distilled water atleast twice and vacuum-dried to obtain the powder form of the hybrid ofcarvedilol and layered silicates. The content of the carvedilol in thehybrid was 58 wt. % which was calculated from the element analysis data.

According to the present invention, the hybrids of itraconazole,cyclosporine and carvedilol with layered silicates enable to form thestable amorphous state by said drugs, wherein such amorphous stateespecially provides the stability and the consequent characteristics ofvarious solubility for each drug so as to provide an outstanding methodfor enhanced solubility of said drugs compared to conventional methods.

While the present invention has been particularly shown and describedwith reference to exemplary embodiments thereof, it will be understoodby those of ordinary skill in the art that various changes in form anddetails may be made therein without departing from the spirit and scopeof the present invention as defined by the following claims.

1. A hybrid of a drug with a layered silicate, the drug being selectedfrom a group consisting of itraconazole, cyclosporine and carvedilol,where the drug is intercalated between the layers of the layeredsilicate and/or adsorbed onto the surface of the layered silicate.
 2. Ahybrid as defined in claim 1, wherein the drug is itraconazole.
 3. Ahybrid as defined in claim 1, wherein the layered silicate is selectedfrom montmorillonite, beidellite, nontronite, hectorite, saponite,illite, celadonite and glauconite.
 4. A hybrid as defined in claim 1,wherein the layered silicate is selected from montmorillonite,beidellite, saponite, hectorite and illite.
 5. A process for preparingthe hybrid as defined in claim 1, comprising: (1) dispersing a layeredsilicate in an aqueous solution to form an aqueous solution containingthe layered silicate; (2) dissolving a drug in a organic solvent to forman organic solution containing the drug, the organic solvent having asolubility higher than that in said aqueous solution and forming aninterface with said aqueous solution; and (3) mixing and hybridizing inthe interface of said aqueous solution containing the layered silicateand said organic solution containing the drug to intercalate said druginto the interlayers of said layered silicate, wherein the drug isselected from a group consisting of itraconazole, cyclosporine andcarvedilol.
 6. A process as defined in claim 5, wherein a solubility ofthe drug in the organic solvent is at least 10 times higher than that inthe aqueous solution.
 7. A process as defined in claim 5, wherein theinterfacial reaction is processed under an acidic condition.
 8. Aprocess as defined in claim 5, wherein pH of the aqueous solutioncontaining the layered silicate in step (1) is between about 0 and about6.
 9. A process as defined in claim 8, wherein pH of the aqueoussolution containing the layered silicate in step (1) is between about 1and about
 4. 10. A process as defined in claim 5, wherein a content ofthe layered silicate in the aqueous solution in step (1) is betweenabout 1% and about 10% by weight.
 11. A process as defined in claim 5,wherein a content of the 3% by weight.
 12. A process as defined in claim5, wherein a content of the drug in the organic solution in step (2) isbetween about 1% and about 30% by weight.
 13. A process as defined inclaim 5, wherein an amount of the organic solvent is such that aconcentration of the layered silicate in the aqueous solution is 30% orless, and an amount of the drug in the organic solvent is 900% or lessthan that of the layered silicate.
 14. A hybrid obtained by mixingEudragit E100® dissolved in an organic solvent with the hybrid ofitraconazole with the layered silicate as defined in claims 1, theamount of said Eudragit E100® being at least 10 by weight based on theweight of itraconazole.
 15. A hybrid obtained by mixing a aqueoussolution of hydroxypropyl methyl cellulose (HPMC) with the hybrid asdefined in claim 14, the amount of said HPMC being is at least 0.5 byweight based on the weight of itraconazole.